Oropharyngeal candidiasis (OPC) is an emerging disorder owing to the prevalence of AIDS, misuse of antibiotics, and host immunosuppression in general. Candida albicans is the most common fungal species isolated from OPC lesions. Recent findings show that mucosal epithelial cells synthesize and secrete antibacterial and antifungal agents, belonging to a family of small, cationic peptides. These molecules, human beta-defensins 1 and 2 (hBD-1, hBD-2) are predicted to function as a first line of host defense against microbial pathogenesis. The PI has discovered that these peptides are expressed in normal human gingival epithelial cells and associated with differentiated epithelium of oral tissues. Moreover, they found that the non oral, yet disseminating isolate C. albicans strain SC5314 stimulates beta-defensin expression in oral epithelial cells, but a clinical OPC isolate does not. This proposal intends to test hypotheses relevant to oropharyngeal candidiasis emanating from the postulate that oral epithelial cells can be stimulated to produce beta-defensins that protect the host from candidal challenges at the oral mucosal barrier. The objectives of this proposal are (1) to determine beta-defensin expression in oral epithelial cells in response to challenge with OPC derived C. albicans isolates, (2) to characterize key virulence factors of C. albicans SC5314 and OPC isolates that lead to beta-defensin response, (3) to examine beta-defensin protection against C. albicans, and (4) to identify genes in oral epithelial cells associated with C. albicans modulation of beta-defensin expression, using microarray technology. The PI hypothesizes that peptide-based antimicrobial defense may be a way in which the gingival epithelium resists invasion of potential pathogens. In light of the frequent adjunctive use of antibiotics and antimycotics in treating oral diseases, with the threat of microbial resistance, investigations into novel eukaryotic peptides, such as beta-defensins, are highly significant and offer the potential for future clinical promise. The PI states that this research direction may be significant in leading to future studies with potential application to oral disorders, therapeutic use, and technology development.